Abstract
Cav3 T-type channels are low-voltage-gated channels with rapid kinetics that are classified among the calcium-selective Cav1 and Cav2 type channels. Here, we outline the fundamental and unique regulators of T-type channels. An ubiquitous and proximally located “gating brake” works in concert with the voltage-sensor domain and S6 alpha-helical segment from domain II to set the canonical low-threshold and transient gating features of T-type channels. Gene splicing of optional exon 25c (and/or exon 26) in the short III–IV linker provides a developmental switch between modes of activity, such as activating in response to membrane depolarization, to channels requiring hyperpolarization input before being available to activate. Downstream of the gating brake in the I–II linker is a key region for regulating channel expression where alternative splicing patterns correlate with functional diversity of spike patterns, pacemaking rate (especially in the heart), stage of development, and animal size. A small but persistent window conductance depolarizes cells and boosts excitability at rest. T-type channels possess an ion selectivity that can resemble not only the calcium ion exclusive Cav1 and Cav2 channels but also the sodium ion selectivity of Nav1 sodium channels too. Alternative splicing in the extracellular turret of domain II generates highly sodium-permeable channels, which contribute to low-threshold sodium spikes. Cav3 channels are more ubiquitous among multicellular animals and more widespread in tissues than the more brain centric Nav1 sodium channels in invertebrates. Highly sodium-permeant Cav3 channels can functionally replace Nav1 channels in species where they are lacking, such as in Caenorhabditis elegans.





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Altier C, Garcia-Caballero A, Simms B, You H, Chen L, Walcher J, Tedford HW, Hermosilla T, Zamponi GW (2011) The Cav-beta subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels. Nat Neurosci 14:173–180. doi:10.1038/nn.2712
Anderson PA, Holman MA, Greenberg RM (1993) Deduced amino acid sequence of a putative sodium channel from the scyphozoan jellyfish Cyanea capillata. Proc Natl Acad Sci U S A 90:7419–7423
Anderson D, Mehaffey WH, Iftinca M, Rehak R, Engbers JD, Hameed S, Zamponi GW, Turner RW (2010) Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes. Nat Neurosci 13:333–337. doi:10.1038/nn.2493
Arias JM, Murbartian J, Vitko I, Lee JH, Perez-Reyes E (2005) Transfer of beta subunit regulation from high to low voltage-gated Ca2+ channels. FEBS Lett 579:3907–3912. doi:10.1016/j.febslet.2005.06.008
Arias O II, Vitko I, Fortuna M, Baumgart JP, Sokolova S, Shumilin IA, Van Deusen A, Soriano-Garcia M, Gomora JC, Perez-Reyes E (2008) Characterization of the gating brake in the I–II loop of Ca(v)3.2 T-type Ca(2+) channels. J Biol Chem 283:8136–8144. doi:10.1074/jbc.M708761200
Armstrong CM, Matteson DR (1985) Two distinct populations of calcium channels in a clonal line of pituitary cells. Science 227:65–67
Astori S, Wimmer RD, Prosser HM, Corti C, Corsi M, Liaudet N, Volterra A, Franken P, Adelman JP, Luthi A (2011) The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus. Proc Natl Acad Sci U S A 108:13823–13828. doi:10.1073/pnas.1105115108
Baumgart JP, Vitko I, Bidaud I, Kondratskyi A, Lory P, Perez-Reyes E (2008) I–II loop structural determinants in the gating and surface expression of low voltage-activated calcium channels. PLoS ONE 3:e2976. doi:10.1371/journal.pone.0002976
Bean BP (1985) Two kinds of calcium channels in canine atrial cells. Differences in kinetics, selectivity, and pharmacology. J Gen Physiol 86:1–30
Benarroch EE (2013) HCN channels: function and clinical implications. Neurology 80:304–310. doi:10.1212/WNL.0b013e31827dec42
Bender KJ, Trussell LO (2009) Axon initial segment Ca2+ channels influence action potential generation and timing. Neuron 61:259–271. doi:10.1016/j.neuron.2008.12.004
Birnbaum SG, Varga AW, Yuan LL, Anderson AE, Sweatt JD, Schrader LA (2004) Structure and function of Kv4-family transient potassium channels. Physiol Rev 84:803–833. doi:10.1152/physrev.00039.2003
Boehme R, Uebele VN, Renger JJ, Pedroarena C (2011) Rebound excitation triggered by synaptic inhibition in cerebellar nuclear neurons is suppressed by selective T-type calcium channel block. J Neurophysiol 106:2653–2661. doi:10.1152/jn.00612.2011
Buraei Z, Yang J (2013) Structure and function of the β subunit of voltage-gated Ca2+ channels. Biochim Biophys Acta 1828:1530–1540. doi:10.1016/j.bbamem.2012.08.028
Carbone E, Lux HD (1984) A low voltage-activated calcium conductance in embryonic chick sensory neurons. Biophys J 46:413–418. doi:10.1016/S0006-3495(84)84037-0
Carbone E, Marcantoni A, Giancippoli A, Guido D, Carabelli V (2006) T-type channels-secretion coupling: evidence for a fast low-threshold exocytosis. Pflugers Arch 453:373–383. doi:10.1007/s00424-006-0100-7
Catterall WA (2010) Ion channel voltage sensors: structure, function, and pathophysiology. Neuron 67:915–928
Chausson P, Leresche N, Lambert RC (2013) Dynamics of intrinsic dendritic calcium signaling during tonic firing of thalamic reticular neurons. PLoS ONE 8:e72275. doi:10.1371/journal.pone.0072275
Chemin J, Monteil A, Bourinet E, Nargeot J, Lory P (2001) Alternatively spliced alpha(1G) (Ca(V)3.1) intracellular loops promote specific T-type Ca(2+) channel gating properties. Biophys J 80:1238–1250. doi:10.1016/S0006-3495(01)76100-0
Chen CC, Lamping KG, Nuno DW, Barresi R, Prouty SJ, Lavoie JL, Cribbs LL, England SK, Sigmund CD, Weiss RM, Williamson RA, Hill JA, Campbell KP (2003) Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels. Science 302:1416–1418. doi:10.1126/science.1089268
Chen YH, Li MH, Zhang Y, He LL, Yamada Y, Fitzmaurice A, Shen Y, Zhang H, Tong L, Yang J (2004) Structural basis of the alpha1-beta subunit interaction of voltage-gated Ca2+ channels. Nature 429:675–680. doi:10.1038/nature02641
Chen WK, Liu IY, Chang YT, Chen YC, Chen CC, Yen CT, Shin HS, Chen CC (2010) Ca(v)3.2 T-type Ca2+ channel-dependent activation of ERK in paraventricular thalamus modulates acid-induced chronic muscle pain. J Neurosci 30:10360–10368. doi:10.1523/JNEUROSCI.1041-10.2010
Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, Liu X, Jiang Y, Bao X, Yao Z, Ding K, Lo WH, Qiang B, Chan P, Shen Y, Wu X (2003) Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 54:239–243. doi:10.1002/ana.10607
Cheng RC, Tikhonov DB, Zhorov BS (2010) Structural modeling of calcium binding in the selectivity filter of the L-type calcium channel. Eur Biophys J 39:839–853. doi:10.1007/s00249-009-0574-2
Cheong E, Shin HS (2013) T-type Ca2+ channels in normal and abnormal brain functions. Physiol Rev 93:961–992. doi:10.1152/physrev.00010.2012
Choe W, Messinger RB, Leach E, Eckle VS, Obradovic A, Salajegheh R, Jevtovic-Todorovic V, Todorovic SM (2011) TTA-P2 is a potent and selective blocker of T-type calcium channels in rat sensory neurons and a novel antinociceptive agent. Mol Pharmacol 80:900–910. doi:10.1124/mol.111.073205
Choi J, Park JH, Kwon OY, Kim S, Chung JH, Lim DS, Kim KS, Rhim H, Han YS (2005) T-type calcium channel trigger p21ras signaling pathway to ERK in Cav3.1-expressed HEK293 cells. Brain Res 1054:22–29. doi:10.1016/j.brainres.2005.05.010
Christel C, Lee A (2012) Ca2+-dependent modulation of voltage-gated Ca2+ channels. Biochim Biophys Acta 1820:1243–1252. doi:10.1016/j.bbagen.2011.12.012
Crandall SR, Govindaiah G, Cox CL (2010) Low-threshold Ca2+ current amplifies distal dendritic signaling in thalamic reticular neurons. J Neurosci 30:15419–15429. doi:10.1523/JNEUROSCI.3636-10.2010
Cribbs L (2010) T-type calcium channel expression and function in the diseased heart. Channels (Austin) 4:447–452
Cribbs LL, Lee JH, Yang J, Satin J, Zhang Y, Daud A, Barclay J, Williamson MP, Fox M, Rees M, Perez-Reyes E (1998) Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. Circ Res 83:103–109
Crill WE (1996) Persistent sodium current in mammalian central neurons. Annu Rev Physiol 58:349–362. doi:10.1146/annurev.ph.58.030196.002025
David LS, Garcia E, Cain SM, Thau E, Tyson JR, Snutch TP (2010) Splice-variant changes of the Ca(V)3.2 T-type calcium channel mediate voltage-dependent facilitation and associate with cardiac hypertrophy and development. Channels (Austin) 4:375–389. doi:10.4161/chan.4.5.12874
David LS, Garcia E, Cain SM, Thau E, Tyson JR, Snutch TP (2010) Splice-variant changes of the Ca(V)3.2 T-type calcium channel mediate voltage-dependent facilitation and associate with cardiac hypertrophy and development. Channels (Austin) 4:389–389
Deschenes M, Paradis M, Roy JP, Steriade M (1984) Electrophysiology of neurons of lateral thalamic nuclei in cat: resting properties and burst discharges. J Neurophysiol 51:1196–1219
Di Biase V, Franzini-Armstrong C (2005) Evolution of skeletal type e-c coupling: a novel means of controlling calcium delivery. J Cell Biol 171:695–704. doi:10.1083/jcb.200503077
Domich L, Oakson G, Steriade M (1986) Thalamic burst patterns in the naturally sleeping cat: a comparison between cortically projecting and reticularis neurones. J Physiol 379:429–449
Doyle DA, Morais CJ, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69–77
Dreyfus FM, Tscherter A, Errington AC, Renger JJ, Shin HS, Uebele VN, Crunelli V, Lambert RC, Leresche N (2010) Selective T-type calcium channel block in thalamic neurons reveals channel redundancy and physiological impact of I(T)window. J Neurosci 30:99–109. doi:10.1523/JNEUROSCI.4305-09.2010
Eaholtz G, Scheuer T, Catterall WA (1994) Restoration of inactivation and block of open sodium channels by an inactivation gate peptide. Neuron 12:1041–1048
Emerick MC, Stein R, Kunze R, McNulty MM, Regan MR, Hanck DA, Agnew WS (2006) Profiling the array of Ca(v)3.1 variants from the human T-type calcium channel gene CACNA1G: alternative structures, developmental expression, and biophysical variations. Proteins 64:320–342. doi:10.1002/prot.20877
Engbers JD, Anderson D, Asmara H, Rehak R, Mehaffey WH, Hameed S, McKay BE, Kruskic M, Zamponi GW, Turner RW (2012) Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells. Proc Natl Acad Sci U S A 109:2601–2606. doi:10.1073/pnas.1115024109
Errington AC, Renger JJ, Uebele VN, Crunelli V (2010) State-dependent firing determines intrinsic dendritic Ca2+ signaling in thalamocortical neurons. J Neurosci 30:14843–14853. doi:10.1523/JNEUROSCI.2968-10.2010
Fedulova SA, Kostyuk PG, Veselovsky NS (1985) Two types of calcium channels in the somatic membrane of new-born rat dorsal root ganglion neurones. J Physiol 359:431–446
Gray LS, Macdonald TL (2006) The pharmacology and regulation of T type calcium channels: new opportunities for unique therapeutics for cancer. Cell Calcium 40:115–120
Hagiwara S, Ozawa S, Sand O (1975) Voltage clamp analysis of two inward current mechanisms in the egg cell membrane of a starfish. J Gen Physiol 65:617–644
Heinemann SH, Terlau H, Stuhmer W, Imoto K, Numa S (1992) Calcium channel characteristics conferred on the sodium channel by single mutations. Nature 356:441–443. doi:10.1038/356441a0
Hille B (2001) Selective permeability: independence ion channels of excitable membranes, Third Edition. Sinauer Associates, Incorporated, pp. 441–470
Hosford DA, Clark S, Cao Z, Wilson WA Jr, Lin FH, Morrisett RA, Huin A (1992) The role of GABAB receptor activation in absence seizures of lethargic (lh/lh) mice. Science 257:398–401
House SJ, Potier M, Bisaillon J, Singer HA, Trebak M (2008) The non-excitable smooth muscle: calcium signaling and phenotypic switching during vascular disease. Pflugers Arch 456:769–785. doi:10.1007/s00424-008-0491-8
Huang Z, Lujan R, Kadurin I, Uebele VN, Renger JJ, Dolphin AC, Shah MM (2011) Presynaptic HCN1 channels regulate Cav3.2 activity and neurotransmission at select cortical synapses. Nat Neurosci 14:478–486. doi:10.1038/nn.2757
Jahnsen H, Llinas R (1984) Ionic basis for the electro-responsiveness and oscillatory properties of guinea-pig thalamic neurones in vitro. J Physiol 349:227–247
Jahnsen H, Llinas R (1984) Electrophysiological properties of guinea-pig thalamic neurones: an in vitro study. J Physiol 349:205–226
Kim D, Song I, Keum S, Lee T, Jeong MJ, Kim SS, McEnery MW, Shin HS (2001) Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2+) channels. Neuron 31:35–45
Lambert RC, Bessaih T, Crunelli V, Leresche N (2013) The many faces of T-type calcium channels. Pflugers Arch. doi:10.1007/s00424-013-1353-6
Latour I, Louw DF, Beedle AM, Hamid J, Sutherland GR, Zamponi GW (2004) Expression of T-type calcium channel splice variants in human glioma. Glia 48:112–119. doi:10.1002/glia.20063
Latour I, Louw DF, Beedle AM, Hamid J, Sutherland GR, Zamponi GW (2004) Expression of T-type calcium channel splice variants in human glioma. Wiley Subscription Services, Inc., A Wiley Company, pp. 112–119
Lee JH, Daud AN, Cribbs LL, Lacerda AE, Pereverzev A, Klockner U, Schneider T, Perez-Reyes E (1999) Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family. J Neurosci 19:1912–1921
Liang J, Zhang Y, Chen Y, Wang J, Pan H, Wu H, Xu K, Liu X, Jiang Y, Shen Y, Wu X (2007) Common polymorphisms in the CACNA1H gene associated with childhood absence epilepsy in Chinese Han population. Ann Hum Genet 71:325–335. doi:10.1111/j.1469-1809.2006.00332.x
Liebeskind BJ, Hillis DM, Zakon HH (2011) Evolution of sodium channels predates the origin of nervous systems in animals. Proc Natl Acad Sci U S A 108:9154–9159. doi:10.1073/pnas.1106363108
Lin YC, Spencer AN (2001) Calcium currents from jellyfish striated muscle cells: preservation of phenotype, characterisation of currents and channel localisation. J Exp Biol 204:3717–3726
Liu JH, Konig S, Michel M, Arnaudeau S, Fischer-Lougheed J, Bader CR, Bernheim L (2003) Acceleration of human myoblast fusion by depolarization: graded Ca2+ signals involved. Development 130:3437–3446
Llinas R, Jahnsen H (1982) Electrophysiology of mammalian thalamic neurones in vitro. Nature 297:406–408
Llinas R, Yarom Y (1981) Electrophysiology of mammalian inferior olivary neurones in vitro. Different types of voltage-dependent ionic conductances. J Physiol 315:549–567
Long SB, Campbell EB, Mackinnon R (2005) Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science 309:903–908. doi:10.1126/science.1116270
Lory P, Bidaud I, Chemin J (2006) T-type calcium channels in differentiation and proliferation. Cell Calcium 40:135–146. doi:10.1016/j.ceca.2006.04.017
Mackie GO, Meech RW (1985) Separate sodium and calcium spikes in the same axon. Nature 313:791–793
Magee JC, Johnston D (1995) Synaptic activation of voltage-gated channels in the dendrites of hippocampal pyramidal neurons. Science 268:301–304
Mangoni ME, Traboulsie A, Leoni AL, Couette B, Marger L, Le Quang K, Kupfer E, Cohen-Solal A, Vilar J, Shin HS, Escande D, Charpentier F, Nargeot J, Lory P (2006) Bradycardia and slowing of the atrioventricular conduction in mice lacking CaV3.1/alpha1G T-type calcium channels. Circ Res 98:1422–1430. doi:10.1161/01. RES.0000225862.14314.49
Markram H, Sakmann B (1994) Calcium transients in dendrites of neocortical neurons evoked by single subthreshold excitatory postsynaptic potentials via low-voltage-activated calcium channels. Proc Natl Acad Sci U S A 91:5207–5211
McKay BE, McRory JE, Molineux ML, Hamid J, Snutch TP, Zamponi GW, Turner RW (2006) Ca(V)3 T-type calcium channel isoforms differentially distribute to somatic and dendritic compartments in rat central neurons. Eur J Neurosci 24:2581–2594. doi:10.1111/j.1460-9568.2006.05136.x
Monteil A, Chemin J, Bourinet E, Mennessier G, Lory P, Nargeot J (2000) Molecular and functional properties of the human alpha(1G) subunit that forms T-type calcium channels. J Biol Chem 275:6090–6100
Mor M, Beharier O, Levy S, Kahn J, Dror S, Blumenthal D, Gheber LA, Peretz A, Katz A, Moran A, Etzion Y (2012) ZnT-1 enhances the activity and surface expression of T-type calcium channels through activation of Ras-ERK signaling. Am J Physiol Cell Physiol 303:C192–C203. doi:10.1152/ajpcell.00427.2011
Nowycky MC, Fox AP, Tsien RW (1985) Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316:440–443
Ohkubo T (2005) Identification and electrophysiological characteristics of isoforms of T-type calcium channel Cav3.2 expressed in pregnant human uterus. Cell Physiol Biochem 16:245–254. doi:10.1159/000089850
Ono K, Iijima T (2010) Cardiac T-type Ca(2+) channels in the heart. J Mol Cell Cardiol 48:65–70. doi:10.1016/j.yjmcc.2009.08.021
Park HJ, Park SJ, Ahn EJ, Lee SY, Seo H, Lee JH (2013) Asp residues of the Glu-Glu-Asp-Asp pore filter contribute to ion permeation and selectivity of the Cav3.2 T-type channel. Cell Calcium 54:226–235. doi:10.1016/j.ceca.2013.06.006
Payandeh J, Scheuer T, Zheng N, Catterall WA (2011) The crystal structure of a voltage-gated sodium channel. Nature 475:353–358
Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83:117–161. doi:10.1152/physrev.00018.2002
Perez-Reyes E (2010) Characterization of the gating brake in the I–II loop of CaV3 T-type calcium channels. Channels (Austin) 4:453–458
Perez-Reyes E, Cribbs LL, Daud A, Lacerda AE, Barclay J, Williamson MP, Fox M, Rees M, Lee JH (1998) Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature 391:896–900
Schlief T, Schonherr R, Imoto K, Heinemann SH (1996) Pore properties of rat brain II sodium channels mutated in the selectivity filter domain. Eur Biophys J 25:75–91
Senatore A, Spafford JD (2014) Physiology and pathology of voltage-gated T-type calcium channels. In: Schaffer SW, Wu Songwei, Li Ming (eds) T-type calcium channel in basic and clinical sciences. Springer
Senatore A, Guan W, Stephens RF, Boone AN, Spafford JD (2013) T-Type calcium channels become sodium-permeable using an alternate extracellular turret outside the selectivity filter
Senatore A, Monteil A, van Minnen J, Smit AB, Spafford JD (2013) NALCN ion channels have alternative selectivity filters resembling calcium channels or sodium channels. PLoS ONE 8:e55088. doi:10.1371/journal.pone.0055088
Senatore A, Spafford JD (2010) Transient and big are key features of an invertebrate T-type channel (LCav3) from the central nervous system of Lymnaea stagnalis. J Biol Chem 285:7447–7458. doi:10.1074/jbc.M109.090753
Senatore A, Spafford JD (2012) Gene transcription and splicing of T-type channels are evolutionarily-conserved strategies for regulating channel expression and gating. PLoS ONE 7:e37409. doi:10.1371/journal.pone.0037409
Senatore A, Spafford JD (2013) Expression and characterization of an extant placozoan T-type channel provides insights into the primordial Cav3 gene
Senatore A, Spafford JD (2013) A uniquely adaptable pore is consistent with NALCN being an ion sensor. Channels (Austin) 7:60–68
Senatore A, Zhorov BS, Spafford JD (2012) Cav3 T-type calcium channels. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling
Shcheglovitov A, Kostyuk P, Shuba Y (2007) Selectivity signatures of three isoforms of recombinant T-type Ca2+ channels. Biochim Biophys Acta 1768:1406–1419. doi:10.1016/j.bbamem.2007.02.017
Shcheglovitov A, Vitko I, Bidaud I, Baumgart JP, Navarro-Gonzalez MF, Grayson TH, Lory P, Hill CE, Perez-Reyes E (2008) Alternative splicing within the I–II loop controls surface expression of T-type Ca(v)3.1 calcium channels. FEBS Lett 582:3765–3770. doi:10.1016/j.febslet.2008.10.013
Spafford JD, Spencer AN, Gallin WJ (1998) A putative voltage-gated sodium channel alpha subunit (PpSCN1) from the hydrozoan jellyfish, Polyorchis penicillatus: structural comparisons and evolutionary considerations. Biochem Biophys Res Commun 244:772–780. doi:10.1006/bbrc.1998.8332
Srivastava M, Begovic E, Chapman J, Putnam NH, Hellsten U, Kawashima T, Kuo A, Mitros T, Salamov A, Carpenter ML, Signorovitch AY, Moreno MA, Kamm K, Grimwood J, Schmutz J, Shapiro H, Grigoriev IV, Buss LW, Schierwater B, Dellaporta SL, Rokhsar DS (2008) The Trichoplax genome and the nature of placozoans. Nature 454:955–960. doi:10.1038/nature07191
Steger KA, Shtonda BB, Thacker C, Snutch TP, Avery L (2005) The C. elegans T-type calcium channel CCA-1 boosts neuromuscular transmission. J Exp Biol 208:2191–2203. doi:10.1242/jeb.01616
Talavera K, Nilius B (2006) Biophysics and structure-function relationship of T-type Ca2+ channels. Cell Calcium 40:97–114. doi:10.1016/j.ceca.2006.04.013
Talavera K, Staes M, Janssens A, Klugbauer N, Droogmans G, Hofmann F, Nilius B (2001) Aspartate residues of the Glu-Glu-Asp-Asp (EEDD) pore locus control selectivity and permeation of the T-type Ca(2+) channel alpha(1G). J Biol Chem 276:45628–45635. doi:10.1074/jbc.M103047200
Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss DA (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 19:1895–1911
Tang L, Gamal El-Din TM, Payandeh J, Martinez GQ, Heard TM, Scheuer T, Zheng N, Catterall WA (2014) Structural basis for Ca2+ selectivity of a voltage-gated calcium channel. Nature 505:56–61. doi:10.1038/nature12775
Taylor JT, Zeng XB, Pottle JE, Lee K, Wang AR, Yi SG, Scruggs JA, Sikka SS, Li M (2008) Calcium signaling and T-type calcium channels in cancer cell cycling. World J Gastroenterol 14:4984–4991
Trimarchi T, Pachuau J, Shepherd A, Dey D, Martin-Caraballo M (2009) CNTF-evoked activation of JAK and ERK mediates the functional expression of T-type Ca2+ channels in chicken nodose neurons. J Neurochem 108:246–259. doi:10.1111/j.1471-4159.2008.05759.x
Uebele VN, Nuss CE, Fox SV, Garson SL, Cristescu R, Doran SM, Kraus RL, Santarelli VP, Li Y, Barrow JC, Yang ZQ, Schlegel KA, Rittle KE, Reger TS, Bednar RA, Lemaire W, Mullen FA, Ballard JE, Tang C, Dai G, McManus OB, Koblan KS, Renger JJ (2009) Positive allosteric interaction of structurally diverse T-type calcium channel antagonists. Cell Biochem Biophys 55:81–93. doi:10.1007/s12013-009-9057-4
Vitko I, Bidaud I, Arias JM, Mezghrani A, Lory P, Perez-Reyes E (2007) The I–II loop controls plasma membrane expression and gating of Ca(v)3.2 T-type Ca2+ channels: a paradigm for childhood absence epilepsy mutations. J Neurosci 27:322–330. doi:10.1523/JNEUROSCI.1817–06
Vitko I, Shcheglovitov A, Baumgart JP, Arias O II, Murbartian J, Arias JM, Perez-Reyes E (2008) Orientation of the calcium channel beta relative to the alpha(1)2.2 subunit is critical for its regulation of channel activity. PLoS ONE 3:e3560
Waithe D, Ferron L, Page KM, Chaggar K, Dolphin AC (2011) Beta-subunits promote the expression of Ca(V)2.2 channels by reducing their proteasomal degradation. J Biol Chem 286:9598–9611. doi:10.1074/jbc.M110.195909
Wang F, Gao H, Kubo H, Fan X, Zhang H, Berretta R, Chen X, Sharp T, Starosta T, Makarewich C, Li Y, Molkentin JD, Houser SR (2013) T-type Ca2+ channels regulate the exit of cardiac myocytes from the cell cycle after birth. J Mol Cell Cardiol 62:122–130. doi:10.1016/j.yjmcc.2013.05.016
Weiss N, Hameed S, Fernandez-Fernandez JM, Fablet K, Karmazinova M, Poillot C, Proft J, Chen L, Bidaud I, Monteil A, Huc-Brandt S, Lacinova L, Lory P, Zamponi GW, De Waard M (2012) A Ca(v)3.2/syntaxin-1A signaling complex controls T-type channel activity and low-threshold exocytosis. J Biol Chem 287:2810–2818. doi:10.1074/jbc.M111.290882
Williams SR, Toth TI, Turner JP, Hughes SW, Crunelli V (1997) The ‘window’ component of the low threshold Ca2+ current produces input signal amplification and bistability in cat and rat thalamocortical neurones. J Physiol 505(Pt 3):689–705
Zhang T, Wang Z, Wang L, Luo N, Jiang L, Liu Z, Wu CF, Dong K (2013) Role of the DSC1 channel in regulating neuronal excitability in Drosophila melanogaster: extending nervous system stability under stress. PLoS Genet 9:e1003327. doi:10.1371/journal.pgen.1003327
Zhong X (2006) A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies. Hum Mol Genet 15:1497–1512. doi:10.1093/hmg/ddl068
Zhorov BS, Tikhonov DB (2013) Ligand action on sodium, potassium, and calcium channels: role of permeant ions. Trends Pharmacol Sci. doi:10.1016/j.tips.2013.01.002
Zhou W, Chung I, Liu Z, Goldin AL, Dong K (2004) A voltage-gated calcium-selective channel encoded by a sodium channel-like gene. Neuron 42:101–112
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Senatore, A., Guan, W. & Spafford, J.D. Cav3 T-type channels: regulators for gating, membrane expression, and cation selectivity. Pflugers Arch - Eur J Physiol 466, 645–660 (2014). https://doi.org/10.1007/s00424-014-1449-7
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DOI: https://doi.org/10.1007/s00424-014-1449-7